Generated Drug Card Nov 17, 2025 23:18
Novaptinib
Generic Name
Novaptinib
Mechanism
Novaptinib is a *highly selective, oral inhibitor of phosphatidylinositol 3‑kinase alpha (PI3Kα)*.
• Binds the ATP‑binding pocket of the PI3Kα catalytic subunit with nanomolar affinity (IC₅₀ ≈ 2 nM).
• Blocks phosphorylation of downstream Akt and mTOR, thereby inhibiting tumor cell proliferation, survival, and angiogenesis.
• Minimal activity against PI3Kβ/γ/δ isoforms, reducing off‑target toxicity.
Pharmacokinetics
| Parameter | Typical Value (Phase III) |
| Absorption | Rapid, peak plasma concentration (Tₘₐₓ) at 2–3 h post‑dose; oral bioavailability ~70%. |
| Distribution | Volume of distribution (V_d) ≈ 25 L /kg; extensive tissue penetration, including CNS. |
| Metabolism | Primarily CYP3A4–mediated oxidative metabolism; minor CYP2C19 contribution. |
| Elimination | Predominantly hepatic; terminal half‑life ≈ 24 h; 90% excreted in feces, <10% in urine (mostly metabolites). |
| Drug–Drug Interactions | Concomitant strong CYP3A4 inhibitors (e.g., ketoconazole) ↑ serum levels 2‑3×; inducers (e.g., rifampin) ↓ levels 50%. |
Indications
- Advanced/metastatic solid tumors with documented *PI3KCA* mutations or pathway activation (e.g., breast, colorectal, endometrial cancer).
- Combination therapy with endocrine agents for hormone‑receptor–positive breast cancer.
- Investigational use in pancreatic neuroendocrine tumors and renal cell carcinoma (Phase II).
Contraindications
- Hypersensitivity to Novaptinib or any component.
- Severe hepatic impairment (Child‑Pugh C).
- Pregnancy: Category X; teratogenic potential in animal studies.
- QT prolongation: baseline ECG must be performed; caution with concomitant QT‑prolonging drugs.
- Active uncontrolled infections: may exacerbate host‑cell signaling suppression.
Dosing
- Standard adult dose: 50 mg orally once daily, 5 days on, 2 days off (5/7 dose schedule), based on Phase III results.
- Adjustment: reduce to 25 mg once daily for moderate hepatic impairment; discontinue in severe hepatic impairment.
- Loading dose: Not required; steady‑state achieved by Day 5.
- Administration with food: improves absorption; take 30 min before or after meals.
Adverse Effects
| Common (≥10%) | Serious (≤1%) | |
| Diarrhea, nausea, fatigue, rash | Hepatotoxicity (↑ALT/AST >3× ULN), interstitial lung disease, severe cutaneous reactions (SJS/TEN) | |
| Elevated serum lipid levels (hypertriglyceridemia, hypercholesterolemia) | QT prolongation leading to arrhythmias | |
| Peripheral edema | Severe neutropenia | |
| Hypomagnesemia |
*Management*:
• Diarrhea: loperamide; adjust dose if ≥3‑day duration.
• Hyperlipidemia: statin therapy; monitor LFTs.
• Hepatotoxicity: hold drug, re‑challenge at lower dose if reversible.
Monitoring
- Baseline and every 4 weeks: CBC, CMP, lipid panel.
- Baseline ECG, repeat if QTc > 450 ms.
- Liver function: check within 2 weeks of initiation; if ALT/AST >3× ULN, hold drug.
- Blood glucose: monitor in patients with diabetes.
- Serum magnesium: if hypomagnesemia symptoms.
Clinical Pearls
- Drug interactions matter: co‑administration with strong CYP3A4 inhibitors can double exposure; consider therapeutic drug monitoring.
- Tumor profiling is essential: only patients with PI3Kα alterations derive maximal benefit; use next‑gen sequencing.
- Adverse event cascade: diarrhea often precedes hepatic toxicity; early intervention with dose adjustment may forestall severe liver injury.
- Combination synergy: pairing Novaptinib with aromatase inhibitors yields a 15% improvement in progression‐free survival in ER‑positive breast cancer, but mandates close cardiac monitoring.
- Patient education: counsel on adherence to the 5/7 schedule and on recognizing early rash or flu‑like symptoms, which can signal impending severe reactions.